Drug-induced thrombocytopenia contributes to morbidity and, occasionally, mortality in patients treated with a wide range of medications (Karpatkin, (1971) Am. J. Med. Sci. 262, p. 68). More than 100 different medications have been implicated in drug-induced thrombocytopenia, including heparin, quinine, quinidine and sulfonamide antibiotics (Shulman et al. "Hemostasis and Thrombosis" (ed 2) Philadelphia, Pa., Lippincott (1987) p.452, and Kracke et al. (1943) JAMA 122, p. 168.
Drug-dependent antibodies reactive with platelets have been identified in only a few instances. Curtis et al., (1984) Blood v. 84, n.1, 176-183, applied flow cytometry to the detection of such antibodies induced by sulfonamide antibiotics. Visentin et al. (1990) Transfusion Oct. v. 30 n. 8, 694-700 describes detection of drug-dependent, platelet-reactive antibodies by antigen-capture ELISA and flow cytometry.
The occurrence of fibrinogen receptor antagonist induced-thrombocytopenia has prompted a search for monoclonal antibodies (mAbs) specific for GP IIb/IIIa receptor:receptor antagonist complexes. Monoclonal antibodies capable of detecting alterations in glycoprotein IIb/IIIa upon binding of fibrinogen receptor antagonists to glycoprotein IIb/IIIa are useful in diagnosing patients at risk to developing fibrinogen receptor antagonist-induced thrombocytopenia. The monoclonals can be tagged with fluorescent or radioactive tracers for ease in diagnosis.
The present invention includes monoclonal antibodies which recognize induced binding sites formed on GPIIb/IIIa receptor following association of a fibrinogen receptor antagonist with the GPIIb/IIIa receptor, and a means for identifying, in a patient, the presence of one or more antibodies in GP IIb/IIIa receptor (fibrinogen receptor) antagonist-induced thrombocytopenia which recognize GPIIb/IIIa receptor:GPIIb/IIIa receptor antagonist complexes formed with purified platelets or purified GPIIb/IIIa receptor and a selected GPIIb/IIIa receptor antagonist. Identification of such antibodies identifies the patient as being at risk to development of thrombocytopenia resulting from administration to the patient of the selected GP IIb/IIIa receptor antagonist.
Diagnosis of patients at risk to developing fibrinogen receptor antagonist induced-thrombocytopenia can be implemented using monoclonal antibodies, having fluorescent, nuclear magnetic or radioactive tags, which are specific for GP IIb/IIIa receptor:receptor antagonist complexes. These monoclonal antibodies will associate with the complex unless a patient's plasma sample, when mixed with the complex and the monoclonal antibody, prevents association of the complex with the monoclonal antibody.